The invention relates to the use of nanocrystalline noble metals for the treatment of hyperproliferative skin disorders and diseases such as psoriasis.
In spite of many years of research on the treatment of hyperproliferative skin disorders and diseases such as psoriasis, there are still many patients suffering from such skin diseases for whom treatment regimes have been ineffective. Furthermore, many of the side effects from the medications currently prescribed for the treatment of psoriasis are problematic. Thus, there still remains a need for a safe and effective treatment for hyperproliferative skin disorders and diseases such as psoriasis and keratinization.
The inventors have discovered that nanocrystalline noble metals selected from one or more of silver, gold, platinum and palladium, are effective in the treatment of psoriasis. Preferably, these noble metals are formed with atomic disorder, such that ions, clusters, atoms or molecules of the metals are released on a sustainable basis.
The nanocrystalline forms of these noble metals may be used in any of the following formats:
i) nanocrystalline coatings of the noble metals on medical grade substrates, for example, dressings, fibers, and materials composed of for example polyethylene, high density polyethylene, polyvinylchloride, latex, silicone, cotton, rayon, polyester, nylon, cellulose, acetate, carboxymethylcellulose, alginate, chitin, chitosan and hydrofibers;
ii) gels, formulated with nanocrystalline powders of the noble metals with such materials as carboxymethylcellulose, alginate, chitin, chitosan and hydrofibers, together with such ingredients as pectin and viscosity enhancers;
iii) creams, lotions, pastes and ointments formulated with nanocrystalline powders of the noble metals, for example as emulsions or with drying emollients;
iv) liquids, formulated as solutions by dissolving nanocrystalline coatings or powders of the noble metals, for example as topical solutions, aerosols or mists;
v) powders, prepared as nanocrystalline powders of the noble metals, or as nanocrystalline coatings of the noble metals on biocompatible substrates in powder form, preferably on bioabsorbable and/or hygroscopic substrates such as:
Synthetic Bioabsorbable Polymers: for example polyesters/polyactones such as polymers of polyglycolic acid, glycolide, lactic acid, lactide, dioxanone, trimethylene carbonate etc., polyanhydrides, polyesteramides, polyortheoesters, polyphosphazenes, and copolymers of these and related polymers or monomers.
Naturally Derived Polymers:
Proteins: albumin, fibrin, collagen, elastin;
Polysaccharides: chitosan, alginates, hyaluronic acid; and
Biosynthetic Polyesters: 3-hydroxybutyrate polymers.
In the above formats, the nanocrystalline noble metals are formulated from nanocrystalline coatings or nanocrystalline powders of the nanocrystalline noble metals, or from solutions prepared by dissolving the nanocrystalline coatings or powders therein. The formulations include a therapeutically effective amount of the coatings or powders, and most preferably, the following amounts:
For coatings: 150-3000 nm thick coatings
For gels, creams and lotions: 0.01-5% by weight of the nanocrystalline noble metal powder
For liquids 0.001-1% by weight of the noble metal
Nanocrystalline coatings of the noble metals are most preferably deposited onto one or more layers of medical dressing materials which can be laminated with uncoated layers of medical dressing materials. The coatings can be prepared by known techniques for preparing nanocrystalline coatings, but are most preferably prepared by physical vapour deposition under conditions which create atomic disorder. The nanocrystalline coatings are most preferably prepared to create an interference colour so as to provide an indicator, as described in prior patent application WO 98/41095, published Sep. 24, 1998, and naming inventors R. E. Burrell and R. J. Precht.
Nanocrystalline powders of the noble metals may be prepared as nanocrystalline coatings, preferably of the above thickness, on powdered substrates such as chitin, or may be prepared as nanocrystalline coatings on a substrate such as a silicon wafer, and then scraped off as a nanocrystalline powder. Alternatively, fine grained or nanocrystalline powders of the noble metals may be cold worked to impart atomic disorder, as disclosed in prior patent application WO 93/23092, published Nov. 25, 1993, naming Burrell et al., as inventors.
As used herein and in the claims, the terms and phrases set out below have the meanings which follow.
xe2x80x9cMetalxe2x80x9d or xe2x80x9cmetalsxe2x80x9d includes one or more metals whether in the form of substantially pure metals, alloys or compounds such as oxides, nitrides, borides, sulphides, halides or hydrides.
xe2x80x9cNoble metalsxe2x80x9d are silver, gold, platinum and palladium, or mixtures of such metals with same or other metals, with silver metal being the most preferred.
xe2x80x9cBiocompatiblexe2x80x9d means non-toxic for the intended utility. Thus, for human utility, biocompatible means non-toxic to humans or human tissues.
xe2x80x9cSustained releasexe2x80x9d or xe2x80x9csustainable basisxe2x80x9d are used to define release of atoms, molecules, ions or clusters of a noble metal that continues over time measured in hours or days, and thus distinguishes release of such metal species from the bulk metal, which release such species at a rate and concentration which is too low to be therapeutically effective, and from highly soluble salts of noble metals such as silver nitrate, which releases silver ions virtually instantly, but not continuously, in contact with an alcohol or electrolyte.
xe2x80x9cAtomic disorderxe2x80x9d includes high concentrations of: point defects in a crystal lattice, vacancies, line defects such as dislocations, interstitial atoms, amorphous regions, grain and sub grain boundaries and the like relative to its normal ordered crystalline state. Atomic disorder leads to irregularities in surface topography and inhomogeneities in the structure on a nanometer scale. xe2x80x9cNormal ordered crystalline statexe2x80x9d means the crystallinity normally found in bulk metal materials, alloys or compounds formed as cast, wrought or plated metal products. Such materials contain only low concentrations of such atomic defects as vacancies, grain boundaries and dislocations.
xe2x80x9cDiffusionxe2x80x9d, when used to describe conditions which limit diffusion in processes to create and retain atomic disorder, i.e. which freeze-in atomic disorder, means diffusion of atoms (adatom diffusion) and/or molecules on the surface or in the matrix of the material being formed.
xe2x80x9cAlcohol or water-based electrolytexe2x80x9d is meant to include any alcohol, water, or water-based electrolyte that the anti-microbial materials of the present invention might contact in order to activate (i.e. cause the release of species of the anti-microbial metal) into same. The term is meant to include alcohols, water, gels, fluids, solvents, and tissues containing water, including body fluids (for example blood, urine or saliva), and body tissue (for example skin, muscle or bone).
xe2x80x9cBioabsorbablexe2x80x9d as used herein in association includes substrates which are useful in medical devices, that is which are biocompatible, and which are capable of bioabsorption in period of time ranging from hours to years, depending on the particular application.
xe2x80x9cBioabsorptionxe2x80x9d means the disappearance of materials from their initial application site in the body (human or mammalian) with or without degradation of the dispersed polymer molecules.
xe2x80x9cColour changexe2x80x9d is meant to include changes of intensity of light under monochromatic light as well as changes of hue from white light containing more than one wavelength.
An xe2x80x9cinterference colourxe2x80x9d is produced when light impinges on two or more partly reflective surfaces separated by a distance which bears the right relationship to the wavelength of the light to be removed by destructive interference.
xe2x80x9cPartly reflectivexe2x80x9d when used to describe the base or top layer materials, means that the material has a surface which reflects a portion of incident light, but which also transmits a portion of the incident light. Reflection occurs when a ray of incoming light encounters a boundary or interface characterized by a change in refractive index between two media. For the top layer of the anti-microbial materials of this invention, that interface is with air. For the base layer, the interface is with the top layer. The reflectance of the base and top layers is balanced so as to generate an interference colour.
xe2x80x9cPartly light transmissivexe2x80x9d when used to describe a thin film of the top layer material means that the thin film is capable of transmitting at least a portion of incident visible light through the thin film.
xe2x80x9cDetectablexe2x80x9d when used to describe a colour change means an observable shift in the dominant wavelength of the reflected light, whether the change is detected by instrument, such as a spectrophotometer, or by the human eye. The dominant wavelength is the wavelength responsible for the colour being observed.
xe2x80x9cCold workingxe2x80x9d as used herein indicates that the material has been mechanically worked such as by milling, grinding, hammering, mortar and pestle or compressing, at temperatures lower than the recrystallization temperature of the material. This ensures that atomic disorder imparted through working is retained in the material.
xe2x80x9cTherapeutically effective amountxe2x80x9d is used herein to denote any amount of a formulation of the nanocrystalline noble metals which will exhibit an antiproliferative effect in a hyperproliferative skin disorder or disease such as psoriasis when applied to the affected area. A single application of the formulations of the present invention may be sufficient, or the formulations may be applied repeatedly over a period of time, such as several times a day for a period of days or weeks. The amount of the active ingredient, that is the nanocrystalline noble metal in the form of a coating, powder or dissolved in liquid solution, will vary with the conditions being treated, the stage of advancement of the condition, and the type and concentration of the formulation being applied. Appropriate amounts in any given instance will be readily apparent to those skilled in the art or capable of determination by routine experimentation.
xe2x80x9cNanocrystallinexe2x80x9d is used herein to denote single-phase or multi-phase polycrystals, the grain size of which is less than about 100, more preferably  less than 50 and most preferably  less than 25 nanometers in at least one dimension. The term, as applied to the crystallite or grain size in the crystal lattice of coatings, powders or flakes of the noble metals, is not meant to restrict the particle size of the materials when used in a powder form.
xe2x80x9cPowderxe2x80x9d is used herein to include particulate sizes of the nanocrystalline noble metals ranging from nanocrystalline powders to flakes.
xe2x80x9cGrain sizexe2x80x9d, or xe2x80x9ccrystallite sizexe2x80x9d means the size of the largest dimension of the crystals in the noble metal coating or powder.
xe2x80x9cHyperproliferative skin disordersxe2x80x9d is used herein to include psoriasis and its varied clinical forms, Reiter""s syndrome, pityriasis rubra pilaris, and hyperproliferative variants of the disorders of keratinization.
xe2x80x9cAntiproliferativexe2x80x9d is used herein to denote effects on the skin including, but not limited to decreasing inflammation, to retarding or normalizing epidermal proliferation and keratinization to produce beneficial effects on hyperproliferative disorders of the skin.